A role for FcγRIIB in the development of murine bleomycin-induced fibrosis

Kaori Sawada; Yasuhito Hamaguchi; Kie Mizumaki; Kyosuke Oishi; Shintaro Maeda; Yuka Ikawa; Akito Komuro; Kazuhiko Takehara; Takashi Matsushita

doi:10.1016/j.jdermsci.2021.11.002

A role for FcγRIIB in the development of murine bleomycin-induced fibrosis

J Dermatol Sci. 2021 Dec;104(3):201-209. doi: 10.1016/j.jdermsci.2021.11.002. Epub 2021 Nov 9.

Authors

Kaori Sawada¹, Yasuhito Hamaguchi², Kie Mizumaki¹, Kyosuke Oishi¹, Shintaro Maeda¹, Yuka Ikawa¹, Akito Komuro³, Kazuhiko Takehara¹, Takashi Matsushita¹

Affiliations

¹ Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
² Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: yasuhito@med.kanazawa-u.ac.jp.
³ Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Department of Plastic Surgery, Kanazawa University Hospital, Kanazawa, Japan.

PMID: 34844843
DOI: 10.1016/j.jdermsci.2021.11.002

Abstract

Background: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive fibrosis. FcγRIIB is a low-affinity receptor for the Fc fragment of IgG. FcγRIIB is expressed on the surface of various leukocyte subsets and signals negative feedback pathways to down-regulate B-cell antigen receptor signaling.

Objective: The aim of the present study was to investigate the role of FcγRIIB in the development of a murine bleomycin-induced scleroderma model.

Methods: The experimental fibrosis model was generated by the intradermal injection of bleomycin into wild-type (WT) and FcγRIIB-deficient (FcγRIIB^-/-) mice. We histologically assessed skin and lung fibrosis as well as inflammatory cell infiltration. Cytokine and chemokine expression levels were measured with RT-PCR.

Results: The severity of fibrosis in the skin and lung was significantly worse in FcγRIIB^-/- mice than in WT mice. In the skin of bleomycin-treated mice, the numbers of CD8⁺ T cells, F4/80⁺ macrophages, MPO⁺ neutrophils, NK1.1⁺NK cells, and B220⁺ B cells were significantly higher in FcγRIIB^-/- mice than in WT mice. The expression of TNF-α and IL-1β was significantly higher in FcγRIIB^-/- mice than in WT mice as was the expression of ICAM-1, CXCL2, and CCL3 in the affected skin. An adoptive transfer of splenic leukocytes from FcγRIIB^-/- mice into WT mice showed exacerbated skin and lung fibrosis compared to WT mice without an adoptive transfer.

Conclusion: These results indicate that FcγRIIB plays an inhibitory role in skin and lung fibrosis. Moreover, modulating FcγRIIB signaling has potential as a therapeutic approach for SSc.

Keywords: Bleomycin; FcγRIIB; Fibrosis.

MeSH terms

Animals
Bleomycin* / toxicity
CD8-Positive T-Lymphocytes / metabolism
Disease Models, Animal
Fibrosis
Mice
Scleroderma, Systemic* / pathology
Skin / pathology

Substances

Bleomycin